In the field of blood transfusion, a leukocyte reduced blood transfusion method, which removes leukocytes in a blood product and transfuses the leukocyte reduced blood product to the recipient, has been widely used in recent years. This is because it was found that relatively slight side effects accompanying blood transfusion, such as headache, nausea, chill, and febrile nonhemolytic reaction, or serious side effects which seriously affect a recipient, such as alloantigen sensitization, viral infection, and post-transfusion graft versus host disease (GVHD), are mainly caused by leukocytes contained in the blood product used for blood transfusion.
It is considered that relatively slight side effects such as headache, nausea, chill, and fever can be prevented by removing leukocytes in the blood product until the leukocyte residual rate becomes 10−1 to 10−2 or less. In order to prevent serious side effects such as alloantigen sensitization and viral infection, it is also considered that leukocytes must be removed until the residual rate becomes 10−4 to 10−6 or less.
The methods for removing leukocytes in a blood product are roughly classified into two kinds of methods of a centrifugal method in which leukocytes are separated and removed using a centrifuge by utilizing the difference in specific gravity among blood components, and a filtering method in which leukocytes are removed by means of adhesion or adsorption using a filter material comprising fiber mass such as nonwoven fabric, a porous structure having continuous pores or the like. The filtering method which removes leukocytes by means of adhesion or adsorption has advantages such as simple operation and low cost, and is most widely used at present.
The leukocyte removal mechanism by the filter material comprising fiber mass such as nonwoven fabric or a porous structure having continuous pores may be considered that leukocytes contacted with the surface of the filter material adhere to or are adsorbed on the surface of the filter material. As a means for improving the leukocyte removal performance of the conventional filter material, studies have been made to increase the contact frequency of the filter material and leukocytes, that is, to increase the surface area per unit volume of the filter material by reducing the fiber diameter or the pore size of the filter material or increasing the bulk density.
Patent document 1 discloses a leukocyte removal filter using nonwoven fabric having a fiber diameter of less than 3 μm and a bulk density of more than 0.15 g/cm3 to not more than 0.50 g/cm3. Although the above leukocyte removal filter exhibits a certain leukocyte removal performance, an increase in liquid flow resistance and clogging of the filter material tend to occur depending on progress of filtration time, whereby problems, for example an extension of filtration time, suspension of filtration, and inferior blood product recovery occur.
In order to solve the above problems, studies have firstly been made to control the clogging of the filter material due to aggregates in a blood product. Patent document 2 discloses a leukocyte removal filter comprising a set of three types of filter materials in which the product XY of the average fiber diameter X and the average fiber-to-fiber distance Y is specified. This leukocyte removal filter efficiently removes aggregates and leukocytes by indispensably providing a three-layer structure in which a filter material with XY>50 is disposed upstream to capture relatively large microaggregates, a filter material with 50≧XY>7 is disposed downstream of the filter material with XY>50 to capture relatively small microaggregates, and a filter material with 7≧XY is disposed downstream of the filter material with 50≧XY>7.
Patent document 3 discloses a filter in which a filter material which removes gel-like aggregates is disposed upstream of the filter, a filter material which removes microaggregates is disposed downstream of the filter material which removes gel-like aggregates, and a filter material which removes leukocytes is disposed downstream of the filter material which removes microaggregates.
Patent document 4 discloses a filter in which clogging of a filter with microaggregates is controlled by disposing filter materials upstream of the filter that has a lower bulk density than filter materials disposed downstream of the filter.
Though clogging of the filter material due to microaggregates in a blood product can be controlled by using the above technologies, recently an improvement in leukocyte removal performance has been increasingly demanded. Specifically, the leukocyte removal performance of a leukocyte removal rate of 99.99% has been demanded as the standard level. This demand may be dealt with by reducing the fiber diameter of the leukocyte removal filter material layer or the pore diameter of the filter material or increasing the bulk density. As a result, additional new problem that the leukocyte removal filter material layer is clogged with blood cell components (particularly leukocytes and platelets) and plasma proteins (particularly fibrin) occurs. The above technologies are effective for controlling clogging of the prefilter layer caused by aggregates, but are insufficient for suppressing clogging of the leukocyte removal filter material layer caused by blood cell components.
In order to solve this problem, technologies relating to leukocyte removal filter materials combining nonwoven fabrics with different properties have been disclosed. Patent document 5 discloses a filter including a first filter material having an average fiber diameter of 0.3 to 1.6 μm and a second filter material having an average fiber diameter larger than that of the first filter material and disposed upstream of the first filter material. The inventors of the present invention have found that the technology disclosed in the patent document 5 reduces clogging of the first filter material, but does not necessarily solve suspicion of clogging of the second filter material.
Moreover, a change in market environment has posed still another problem. Conventionally, a method has been generally employed in which leukocytes are removed at a hospital bedside from blood subjected to cold storage (stored for six weeks at most) after collection. However, it has become general practice in most Western blood centers to remove leukocytes before storage (prestorage leukocyte reduction) in order to improve the quality of the blood product and manage the leukocyte removal process. As a blood filtration using the prestorage leukocyte reduction, ambient temperature filtration in which blood is filtered at an ambient temperature within one day after collection, and cold filtration in which blood is filtered after storing the blood in a refrigerator for about 1 to 3 days are generally used. While ambient temperature filtration exhibits a reduced filtration time, leakage of leukocytes easily occurs in comparison with blood subjected to cold storage. Cold filtration relatively prevents leakage of leukocytes, although the filtration time is long. Accordingly, a filter used under these conditions is required to achieve a reduction in filtration time in cold filtration and an improvement in leukocyte removal performance in ambient temperature filtration.
A leukocyte removal filter which can be used under ambient temperature filtration conditions and cold filtration conditions has not yet been obtained. Specifically, since the patent document 5 is not aware of such a demand, the leukocyte removal performance may become insufficient in ambient temperature filtration.
Patent document 6 discloses a filter in which the fiber diameter of a second filter material on the blood outlet side is defined in the range of 50% to 90% of the fiber diameter of a first filter material on the blood inlet side. According to the studies conducted by the inventors of the present invention, since the first and second filter materials disclosed in the patent document 6 have fiber diameters close to each other, the difference in the function of the filter materials is deficient, whereby the first and second filter materials cannot be assigned different functions. Therefore, it has been found that the filter can be exhibited only unbalanced performance, i.e. shortened filtration time or high leukocyte removal performance. As a result, only a filter suitable for either cold filtration or ambient temperature filtration can be provided. Specifically, the patent document 6 is not aware of a demand for a filter which achieves both a high leukocyte removal performance in ambient temperature filtration and a reduction in filtration time in cold filtration.
As described above, it has become necessary to achieve both a high leukocyte removal performance in ambient temperature filtration and a reduction in filtration time in cold filtration in view of the new market environment arising from prestorage leukocyte reduction. However, the prior arts are not aware of such a demand. Therefore, a filter exhibiting excellent performance under both ambient temperature filtration conditions and cold filtration conditions has not yet been provided, and a leukocyte removal method using such a leukocyte removal filter has not been known.    [Patent document 1] JP-A-S60-193468    [Patent document 2] JP-A-H01-236064    [Patent document 3] U.S. Pat. No. 4,925,572    [Patent document 4] JP-A-H03-173824    [Patent document 5] JP-A-H05-17361    [Patent document 6] JP-A-2002-204910